Cognitive disorders are a common type of neurological disorders. For example, dementia is form of impaired cognition caused by brain dysfunction. The hallmark of most forms of dementia is the disruption of memory performance. Among the several conditions labeled as dementia, the most common are Alzheimer's disease and mild cognitive impairment (MCI), which is a pre-clinical form of Alzheimer's disease. MCI is an intermediate state between normal aging and dementia and is characterized by acquired cognitive deficits, without significant decline in functional activities of daily living. Subjects with MCI and the initial phase of Alzheimer's disease originally present with a predominant deficit in memory function. In more advanced stages of Alzheimer's disease, impairment in additional cognitive domains culminate with a significant decline in quality of life and the inability to perform usual daily activities.
Alzheimer's disease is one of the most common cognitive disorders in humans and has an exponentially increasing incidence. Although the defining characteristic of Alzheimer's disease is cognitive impairment, it is often accompanied by mood and behavioral symptoms such as depression, anxiety, irritability, inappropriate behavior, sleep disturbance, psychosis, and agitation. Neuro-imaging and genetic testing have aided in the identification of individuals at increased risk for dementia. However, the measurement of change in cognitive and functional status in, for example, MCI remains challenging because it requires instruments that are more sensitive and specific than those considered adequate for research in dementia. Accordingly, no treatment exists that adequately prevents or cures Alzheimer's disease or MCI.
Alzheimer's disease and MCI are already a public health problem of enormous proportions. It is estimated that 5 million people currently suffer with Alzheimer's disease in the United States. This figure is likely underestimated due to the high number of unrecognized and undiagnosed patients in the community. By the year 2050, Alzheimer's is projected to affect 14 million people. Moreover, because the prevalence of Alzheimer's disease doubles every 5 years after age 65, the impact of the disease on society tends to increase with the growth of the elderly population. The annual cost in the United States of AD alone is approximately $100 billion.
There is currently no effective treatment for the memory loss and other cognitive deficits presented by patients with dementia, particularly Alzheimer's disease. Treating Alzheimer's disease tends to be more challenging than other neurological disorders because Alzheimer's largely affects a geriatric population. Oral medications including Acetylcholinesterase inhibitors and cholinergic agents are the mainstay treatment for this condition. Nevertheless, the outcome with these agents is modest and tends to decline as the disease progresses. Other agents, such as nonsteroidal anti-inflammatory drugs, corticosteroids, COX-2 inhibitors, estrogen, and antioxidants, have also been tried with poor results. Neurotrophic factors (molecules that increase survival and growth of neurons in laboratory experiments) have been recently used clinically for Alzheimer's disease. Because these agents are proteins, they are inactive with oral administration and cannot cross the blood-brain barrier when administered systemically. When infused intraventricularly in three patients with Alzheimer's disease, nerve growth factor (NGF) increased cerebral nicotine binding. However, this compound had only modest clinical effects and was associated with back pain and weight loss that were reversible with the cessation of treatment.
Alternative routes of neurotrophic factor administration are currently being studied. Gene therapy and small neurotrophic molecules that can penetrate the blood-brain barrier (AIT-082) are possible methods for drug delivery. Moreover, treatment strategies against beta-amyloid protein accumulation and plaque formation including immunotherapies with vaccines are other possible methods. However, but clinical data is still lacking for any of these alternative methods for treating cognitive disorders.
Most aspects of memory function involve temporal lobe structures. Amnesic syndromes have been described after the disruption of the hippocampus, amygdala, fornix, mammilary bodies, anterior nucleus of the thalamus, rhinal cortex, parahippocampal cortex, and temporal neocortex. These structures are mainly involved with the so-called declarative memory, which comprises the memory for facts, events, spatial location, recognition of forms, significance of data processed, among others. However, no interventions within the temporal lobe have been successful in improving memory function.
The hippocampus also has been found to play a crucial role in learning and memory. Lesions of the hippocampus in rodents, primates and man have been found to impair the process of memory acquisition and its persistence. In addition, the hippocampus receive strong inputs from nuclei in the basal forebrain, including the septal nuclei, the diagonal band of Broca and the nucleus basalis of Meynert and lesions in these structures also impair learning and memory. Dysfunction or pathological changes in these circuits may contribute to memory and learning deficits in a variety of circumstances including old age and Alzheimer's disease. The finding of pathological changes in these structures (including synaptic and neuronal loss, senile plaques and neurofibrillary tangles) is characteristic of both age related and Alzheimer's type memory and learning dysfunction. Since septohippocampal lesions affect new learning to a greater extent than established memories, these structures appear to play an essential facilitory role in the establishment and consolidation of memory. Again, however, no interventions within the hippocampus or related structures have been successful in improving memory function.
It is therefore desirable to provide a technique for preventing or treating cognitive disorders such as Alzheimer's disease and/or, more broadly, to improve cognitive function in patients.